INDO-US Collaboration to Develop Rotavirus Vaccines

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Rotavirus infects all children by 5 years of life, and is the most common cause of severe gastroenteritis worldwide. In the US, rotavirus is a common cause of morbidity, accounting for considerable health-care costs. However, morbidity and mortality are most serious in developing countries. Disease burden studies have established rotavirus as an important cause of diarrhea and death in Indian children. In India, rotavirus is responsible for about 20% of diarrhea related hospitalizations and 100,000 deaths; the annual number ofrotavirus specific hospitalizations is approximately 500,000. First rotavirus infections are associated with the most severe diarrhea, but natural immunity protects against severe diarrhea upon reinfection. Live, oral vaccines protect against severe rotavirus diarrhea of infancy, and several rotavirus vaccines have been developed. The only rotavirus vaccine licensed to date - an oral, live, tetravalent, rhesus-based vaccine -was found to be safe and efficacious in clinical trials. However, it was subsequently withdrawn from the US market because of an increased incidence of intussusception among vaccine recipients. A rotavirus vaccine program is still needed to prevent the global burden of rotavirus associated morbidity and mortality. This is a high priority in developing countries leading to investigation of other vaccines. The proposed study will investigate two live, oral rotavirus candidate vaccines, strains 116E and I321, for prevention of severe rotavirus diarrhea in Indian children. Development of the vaccine strains is based on molecular and epidemiologic evidence that they are naturally occurring human bovine reassortants, circulating in India, with favorable clinical and immunologic profiles. Each of the Indian strains is genotypically distinct and there is no way to determine to superiority of either without conducting the proposed clinical trials. Both will be tested in parallel to define the most viable vaccine candidate (e.g., higher cactogenicity, poor immunogenicity, low efficacy, low yield). Collaborative efforts by investigators at AIIMS (India), IISc (India), Stanford University and CDC are proposed to conduct Phase I, II and [II clinical studies of the Indian strains among Indian infants. This collaboration will provide capacity-building for a vaccine testing and evaluation center at AIIMS. The opportunity to understand host and pathogen-associated factors related to pathogenesis of intussusception is also available through this collaboration. The proposed studies will support future efforts towards vaccine development in India as well as to understanding of adverse events associated with live, oral vaccines.